Mifepristone inhibits GRβ coupled prostate cancer cell proliferation

Martin Ligr, Yirong Li, Susan K. Logan, Samir Taneja, Jonathan Melamed, Hebert Lepor, Michael J. Garabedian, Peng Lee

    Research output: Contribution to journalArticle

    Abstract

    Purpose: The GR gene produces GRα and GRβ isoforms by alternative splicing of a C-terminal exon. GRα binds glucocorticoids, modulates transcription in a glucocorticoid dependent manner and has a growth inhibitory role in prostate cells. Due to this role glucocorticoids are often used to treat androgen independent prostate cancer. In contrast, GRβ has intrinsic transcriptional activity and binds mifepristone (RU486) but not glucocorticoids to control gene expression. To our knowledge the role of GRβ in prostate cell proliferation is unknown. Materials and Methods: We determined GRβ levels in various prostate cancer cell lines by reverse transcriptase-polymerase chain reaction and Western blot. The effect of GRβ on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined after siRNA mediated knockdown and over expression of GRβ. Results: GRβ mRNA and protein were up-regulated in LNCaP cells that over expressed the androgen receptor co-factor ARA70β. Treatment of LNCaP-ARA70β with mifepristone or siRNA targeting GRβ inhibited proliferation compared to that of parental LNCaP cells. The immortal but nontumorigenic RC165 prostate cell line and the tumorigenic DU145 prostate cell line with endogenous GRβ also showed partial growth reduction upon GRβ depletion but to a lesser extent than LNCaP-ARA70β cells. The growth stimulatory effect of ARA70β on LNCaP cells was partly GRβ dependent, as was the proliferation of RC165 cells and to a lesser extent of DU145 cells. Conclusions: Results suggest that patients with a primary tumor that expresses GRβ and ARA70β may benefit from mifepristone.

    Original languageEnglish (US)
    Pages (from-to)981-988
    Number of pages8
    JournalJournal of Urology
    Volume188
    Issue number3
    DOIs
    StatePublished - Sep 2012

    Keywords

    • gene expression
    • glucocorticoid
    • mifepristone
    • prostate
    • prostatic neoplasms
    • receptors

    ASJC Scopus subject areas

    • Urology

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  • Cite this

    Ligr, M., Li, Y., Logan, S. K., Taneja, S., Melamed, J., Lepor, H., Garabedian, M. J., & Lee, P. (2012). Mifepristone inhibits GRβ coupled prostate cancer cell proliferation. Journal of Urology, 188(3), 981-988. https://doi.org/10.1016/j.juro.2012.04.102